tbuckley/cabot-search huggingface dataset:
A field study of the impacts of workplace diversity on the recruitment of minority group members
Authors: Aaron D. Nichols, Jordan Axt, Evelyn Gosnell, Dan Ariely
Journal: Nature Human Behaviour (2023)

Abstract Increasing workplace diversity is a common goal. Given research showing that minority applicants anticipate better treatment in diverse workplaces, we ran a field experiment ( N = 1,585 applicants, N = 31,928 website visitors) exploring how subtle organizational diversity cues affected applicant behaviour. Potential applicants viewed a company with varying levels of racial/ethnic or gender diversity. There was little evidence that racial/ethnic or gender diversity impacted the demographic composition or quality of the applicant pool. However, fewer applications were submitted to organizations with one form of diversity (that is, racial/ethnic or gender diversity), and more applications were submitted to organizations with only white men employees or employees diverse in race/ethnicity and gender. Finally, exploratory analyses found that female applicants were rated as more qualified than male applicants. Presenting a more diverse workforce does not guarantee more minority applicants, and organizations seeking to recruit minority applicants may need stronger displays of commitments to diversity.
C-Reactive Protein, Neutrophil-to-Lymphocyte Ratio, and Long-Term Mortality in Chinese Centenarians
Authors: Qiao Zhu, Qian Zhang, Chen Chen, Miao Liu, Yao He, Yali Zhao, Shihui Fu
Journal: JAMA Network Open (2023)

This cohort study explores whether biomarkers of inflammation-related aging, including C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio, are associated with long-term mortality in Chinese centenarians.
Sociodemographic Disparities and Hearing-Related Quality of Life in Children With Hearing Loss
Authors: Brooke R. Warren, Inderpreet Kaur Khalsa, Jihyun Stephans, Dylan K. Chan
Journal: JAMA Network Open (2023)

This cohort study assesses the association of sociodemographic differences with quality of life in deaf and hard-of-hearing children and adolescents in the US.
Engagement With Mental Health Services Among Survivors of Firearm Injury
Authors: Lauren A. Magee, Damaris Ortiz, Zachary W. Adams, Brigid R. Marriott, Anthony W. Beverly, Beatrice Beverly, Matthew C. Aalsma, Sarah E. Wiehe, Megan L. Ranney
Journal: JAMA Network Open (2023)

Despite the prevalence of posttraumatic stress symptoms after firearm injury, little is known about how firearm injury survivors connect with mental health services.
Benefits of Prokinetics, Gastroparesis Diet, or Neuromodulators Alone or in Combination for Symptoms of Gastroparesis
Authors: William L. Hasler, Allen A. Lee, Baharak Moshiree, Brian C. Surjanhata, Satish Rao, Henry P. Parkman, Linda A. Nguyen, Irene Sarosiek, John M. Wo, Michael I. Schulman, Richard W. McCallum, Braden Kuo
Journal: Clinical Gastroenterology and Hepatology (2023)

Prokinetics have limited effectiveness for treating symptoms of gastroparesis. Thus, alternative or adjunct therapies, such as gastroparesis diets or neuromodulators, are often prescribed. Their therapeutic benefits alone or in combination remain unclear.
Deep immunological imprinting due to the ancestral spike in the current bivalent COVID-19 vaccine
Authors: Qian Wang, Yicheng Guo, Anthony R. Tam, Riccardo Valdez, Aubree Gordon, Lihong Liu, David D. Ho
Journal: Cell Reports Medicine (2023)

To combat the evolving SARS-CoV-2 Omicron variants, bivalent COVID-19 mRNA vaccines, encoding both ancestral and Omicron BA.5 spikes, have replaced monovalent vaccines in numerous countries. However, fourth doses of either vaccine result in similar neutralizing antibody titers against Omicron subvariants, raising the possibility of immunological imprinting. To address this, we investigate antibody responses in 72 participants given three doses of a monovalent mRNA vaccine, followed by a bivalent or monovalent booster, or those with breakthrough infections with BA.5 or BQ. Bivalent boosters do not show notably higher binding or virus-neutralizing titers against various SARS-CoV-2 variants compared to monovalent ones. However, breakthrough infections lead to significantly better neutralization of Omicron subvariants. Multiple analyses, including antigenic mapping, suggest that the ancestral spike in bivalent vaccines is causing deep immunological imprinting, preventing broadening of antibodies to the BA.5 component, thereby defeating its intended goal. Its removal from future vaccine compositions is therefore strongly recommended.
Polygenic risk scores for disease risk prediction in Africa: current challenges and future directions
Authors: Segun Fatumo, Dassen Sathan, Chaimae Samtal, Itunuoluwa Isewon, Tsaone Tamuhla, Chisom Soremekun, James Jafali, Sumir Panji, Nicki Tiffin, Yasmina Jaufeerally Fakim
Journal: Genome Medicine (2023)

Early identification of genetic risk factors for complex diseases can enable timely interventions and prevent serious outcomes, including mortality. While the genetics underlying many Mendelian diseases have been elucidated, it is harder to predict risk for complex diseases arising from the combined effects of many genetic variants with smaller individual effects on disease aetiology. Polygenic risk scores (PRS), which combine multiple contributing variants to predict disease risk, have the potential to influence the implementation for precision medicine. However, the majority of existing PRS were developed from European data with limited transferability to African populations. Notably, African populations have diverse genetic backgrounds, and a genomic architecture with smaller haplotype blocks compared to European genomes. Subsequently, growing evidence shows that using large-scale African ancestry cohorts as discovery for PRS development may generate more generalizable findings. Here, we (1) discuss the factors contributing to the poor transferability of PRS in African populations, (2) showcase the novel Africa genomic datasets for PRS development, (3) explore the potential clinical utility of PRS in African populations, and (4) provide insight into the future of PRS in Africa.
Bacterial genome-wide association study substantiates papGII of Escherichia coli as a major risk factor for urosepsis
Authors: Aline Cuénod, Jessica Agnetti, Helena M. B. Seth-Smith, Tim Roloff, Denise Wälchli, Dimitri Shcherbakov, Rashid Akbergenov, Sarah Tschudin-Sutter, Stefano Bassetti, Martin Siegemund, Christian H. Nickel, Jacob Moran-Gilad, Timothy G. Keys, Valentin Pflüger, Nicholas R. Thomson, Adrian Egli
Journal: Genome Medicine (2023)

Urinary tract infections (UTIs) are among the most common bacterial infections worldwide, often caused by uropathogenic Escherichia coli. Multiple bacterial virulence factors or patient characteristics have been linked separately to progressive, more invasive infections. In this study, we aim to identify pathogen- and patient-specific factors that drive the progression to urosepsis by jointly analysing bacterial and host characteristics.We analysed 1076 E. coli strains isolated from 825 clinical cases with UTI and/or bacteraemia by whole-genome sequencing (Illumina). Sequence types (STs) were determined via srst2 and capsule loci via fastKaptive. We compared the isolates from urine and blood to confirm clonality. Furthermore, we performed a bacterial genome-wide association study (bGWAS) (pyseer) using bacteraemia as the primary clinical outcome. Clinical data were collected by an electronic patient chart review. We concurrently analysed the association of the most significant bGWAS hit and important patient characteristics with the clinical endpoint bacteraemia using a generalised linear model (GLM). Finally, we designed qPCR primers and probes to detect papGII-positive E. coli strains and prospectively screened E. coli from urine samples (n = 1657) at two healthcare centres.Our patient cohort had a median age of 75.3 years (range: 18.00-103.1) and was predominantly female (574/825, 69.6%). The bacterial phylogroups B2 (60.6%; 500/825) and D (16.6%; 137/825), which are associated with extraintestinal infections, represent the majority of the strains in our collection, many of which encode a polysaccharide capsule (63.4%; 525/825). The most frequently observed STs were ST131 (12.7%; 105/825), ST69 (11.0%; 91/825), and ST73 (10.2%; 84/825). Of interest, in 12.3% (13/106) of cases, the E. coli pairs in urine and blood were only distantly related. In line with previous bGWAS studies, we identified the gene papGII (p-value < 0.001), which encodes the adhesin subunit of the E. coli P-pilus, to be associated with 'bacteraemia' in our bGWAS. In our GLM, correcting for patient characteristics, papGII remained highly significant (odds ratio = 5.27, 95% confidence interval = [3.48, 7.97], p-value < 0.001). An independent cohort of cases which we screened for papGII-carrying E. coli at two healthcare centres further confirmed the increased relative frequency of papGII-positive strains causing invasive infection, compared to papGII-negative strains (p-value = 0.033, chi-squared test).This study builds on previous work linking papGII with invasive infection by showing that it is a major risk factor for progression from UTI to bacteraemia that has diagnostic potential.
CHESS 3: an improved, comprehensive catalog of human genes and transcripts based on large-scale expression data, phylogenetic analysis, and protein structure
Authors: Ales Varabyou, Markus J. Sommer, Beril Erdogdu, Ida Shinder, Ilia Minkin, Kuan-Hao Chao, Sukhwan Park, Jakob Heinz, Christopher Pockrandt, Alaina Shumate, Natalia Rincon, Daniela Puiu, Martin Steinegger, Steven L. Salzberg, Mihaela Pertea
Journal: Genome biology (2023)

CHESS 3 represents an improved human gene catalog based on nearly 10,000 RNA-seq experiments across 54 body sites. It significantly improves current genome annotation by integrating the latest reference data and algorithms, machine learning techniques for noise filtering, and new protein structure prediction methods. CHESS 3 contains 41,356 genes, including 19,839 protein-coding genes and 158,377 transcripts, with 14,863 protein-coding transcripts not in other catalogs. It includes all MANE transcripts and at least one transcript for most RefSeq and GENCODE genes. On the CHM13 human genome, the CHESS 3 catalog contains an additional 129 protein-coding genes. CHESS 3 is available at http://ccb.jhu.edu/chess .
Comparison of gene clustering criteria reveals intrinsic uncertainty in pangenome analyses
Authors: Saioa Manzano-Morales, Yang Liu, Sara González-Bodí, Jaime Huerta-Cepas, Jaime Iranzo
Journal: Genome biology (2023)

A key step for comparative genomics is to group open reading frames into functionally and evolutionarily meaningful gene clusters. Gene clustering is complicated by intraspecific duplications and horizontal gene transfers that are frequent in prokaryotes. In consequence, gene clustering methods must deal with a trade-off between identifying vertically transmitted representatives of multicopy gene families, which are recognizable by synteny conservation, and retrieving complete sets of species-level orthologs. We studied the implications of adopting homology, orthology, or synteny conservation as formal criteria for gene clustering by performing comparative analyses of 125 prokaryotic pangenomes.Clustering criteria affect pangenome functional characterization, core genome inference, and reconstruction of ancestral gene content to different extents. Species-wise estimates of pangenome and core genome sizes change by the same factor when using different clustering criteria, allowing robust cross-species comparisons regardless of the clustering criterion. However, cross-species comparisons of genome plasticity and functional profiles are substantially affected by inconsistencies among clustering criteria. Such inconsistencies are driven not only by mobile genetic elements, but also by genes involved in defense, secondary metabolism, and other accessory functions. In some pangenome features, the variability attributed to methodological inconsistencies can even exceed the effect sizes of ecological and phylogenetic variables.Choosing an appropriate criterion for gene clustering is critical to conduct unbiased pangenome analyses. We provide practical guidelines to choose the right method depending on the research goals and the quality of genome assemblies, and a benchmarking dataset to assess the robustness and reproducibility of future comparative studies.
The microbiome and rise of early-onset cancers: knowledge gaps and research opportunities
Authors: Kosuke Mima, Tsuyoshi Hamada, Kentaro Inamura, Hideo Baba, Tomotaka Ugai, Shuji Ogino
Journal: Gut Microbes (2023)

Accumulating evidence indicates an alarming increase in the incidence of early-onset cancers, which are diagnosed among adults under 50 years of age, in the colorectum, esophagus, extrahepatic bile duct, gallbladder, liver, stomach, pancreas, as well as the bone marrow (multiple myeloma), breast, head and neck, kidney, prostate, thyroid, and uterine corpus (endometrium). While the early-onset cancer studies have encompassed research on the wide variety of organs, this article focuses on research on digestive system cancers. While a minority of early-onset cancers in the digestive system are associated with cancer-predisposing high penetrance germline genetic variants, the majority of those cancers are sporadic and multifactorial. Although potential etiological roles of diets, lifestyle, environment, and the microbiome from early life to adulthood (i.e. in one's life course) have been hypothesized, exact contribution of each of these factors remains uncertain. Diets, lifestyle patterns, and environmental exposures have been shown to alter the oral and intestinal microbiome. To address the rising trend of early-onset cancers, transdisciplinary research approaches including lifecourse epidemiology and molecular pathological epidemiology frameworks, nutritional and environmental sciences, multi-omics technologies, etc. are needed. We review current evidence and discuss emerging research opportunities, which can improve our understanding of their etiologies and help us design better strategies for prevention and treatment to reduce the cancer burden in populations.
STIM-mediated calcium influx regulates maintenance and selection of germinal center B cells
Authors: Yutaro Yada, Masanori Matsumoto, Takeshi Inoue, Akemi Baba, Ryota Higuchi, Chie Kawai, Masashi Yanagisawa, Daisuke Kitamura, Shouichi Ohga, Tomohiro Kurosaki, Yoshihiro Baba
Journal: The Journal of Experimental Medicine (2023)

Positive selection of high-affinity germinal center (GC) B cells is driven by antigen internalization through their B cell receptor (BCR) and presentation to follicular helper T cells. However, the requirements of BCR signaling in GC B cells remain poorly understood. Store-operated Ca2+ entry, mediated by stromal interacting molecule 1 (STIM1) and STIM2, is the main Ca2+ influx pathway triggered by BCR engagement. Here, we showed that STIM-deficient B cells have reduced B cell competitiveness compared with wild-type B cells during GC responses. B cell-specific deletion of STIM proteins decreased the number of high-affinity B cells in the late phase of GC formation. STIM deficiency did not affect GC B cell proliferation and antigen presentation but led to the enhancement of apoptosis due to the impaired upregulation of anti-apoptotic Bcl2a1. STIM-mediated activation of NFAT was required for the expression of Bcl2a1 after BCR stimulation. These findings suggest that STIM-mediated survival signals after antigen capture regulate the optimal selection and maintenance of GC B cells.
ATP1A1/BCL2L1 predicts the response of myelomonocytic and monocytic acute myeloid leukemia to cardiac glycosides
Authors: Claudia Cerella, Sruthi Reddy Gajulapalli, Anne Lorant, Deborah Gerard, Florian Muller, Yejin Lee, Kyung Rok Kim, Byung Woo Han, Christo Christov, Christian Récher, Jean-Emmanuel Sarry, Mario Dicato, Marc Diederich
Journal: Leukemia (2023)

Myelomonocytic and monocytic acute myeloid leukemia (AML) subtypes are intrinsically resistant to venetoclax-based regimens. Identifying targetable vulnerabilities would limit resistance and relapse. We previously documented the synergism of venetoclax and cardiac glycoside (CG) combination in AML. Despite preclinical evidence, the repurposing of cardiac glycosides (CGs) in cancer therapy remained unsuccessful due to a lack of predictive biomarkers. We report that the ex vivo response of AML patient blasts and the in vitro sensitivity of established cell lines to the hemi-synthetic CG UNBS1450 correlates with the ATPase Na+/K+ transporting subunit alpha 1 (ATP1A1)/BCL2 like 1 (BCL2L1) expression ratio. Publicly available AML datasets identify myelomonocytic/monocytic differentiation as the most robust prognostic feature, along with core-binding factor subunit beta (CBFB), lysine methyltransferase 2A (KMT2A) rearrangements, and missense Fms-related receptor tyrosine kinase 3 (FLT3) mutations. Mechanistically, BCL2L1 protects from cell death commitment induced by the CG-mediated stepwise triggering of ionic perturbation, protein synthesis inhibition, and MCL1 downregulation. In vivo, CGs showed an overall tolerable profile while impacting tumor growth with an effect ranging from tumor growth inhibition to regression. These findings suggest a predictive marker for CG repurposing in specific AML subtypes.
Localized APP expression results in progressive network dysfunction by disorganizing spike timing
Authors: Silvia Viana da Silva, Matthias G. Haberl, Kshitij Gaur, Rina Patel, Gautam Narayan, Max Ledakis, Maylin L. Fu, Miguel de Castro Vieira, Edward H. Koo, Jill K. Leutgeb, Stefan Leutgeb
Journal: Neuron (2023)

Progressive cognitive decline in Alzheimer's disease could either be caused by a spreading molecular pathology or by an initially focal pathology that causes aberrant neuronal activity in a larger network. To distinguish between these possibilities, we generated a mouse model with expression of mutant human amyloid precursor protein (APP) in only hippocampal CA3 cells. We found that performance in a hippocampus-dependent memory task was impaired in young adult and aged mutant mice. In both age groups, we then recorded from the CA1 region, which receives inputs from APP-expressing CA3 cells. We observed that theta oscillation frequency in CA1 was reduced along with disrupted relative timing of principal cells. Highly localized pathology limited to the presynaptic CA3 cells is thus sufficient to cause aberrant firing patterns in postsynaptic neuronal networks, which indicates that disease progression is not only from spreading pathology but also mediated by progressively advancing physiological dysfunction.
Viral vector-mediated transgene delivery with novel recombinase systems for targeting neuronal populations defined by multiple features
Authors: Minju Jeong, Jun-Hyeok Choi, Hyeonseok Jang, Dong Hyun Sohn, Qingdi Wang, Joann Lee, Li Yao, Eun Ji Lee, Jiachen Fan, Marta Pratelli, Eric H. Wang, Christen N. Snyder, Xiao-yun Wang, Sora Shin, Aryn H. Gittis, Tsung-Chang Sung, Nicholas C. Spitzer, Byung Kook Lim
Journal: Neuron (2023)

A comprehensive understanding of neuronal diversity and connectivity is essential for understanding the anatomical and cellular mechanisms that underlie functional contributions. With the advent of single-cell analysis, growing information regarding molecular profiles leads to the identification of more heterogeneous cell types. Therefore, the need for additional orthogonal recombinase systems is increasingly apparent, as heterogeneous tissues can be further partitioned into increasing numbers of specific cell types defined by multiple features. Critically, new recombinase systems should work together with pre-existing systems without cross-reactivity in vivo. Here, we introduce novel site-specific recombinase systems based on ΦC31 bacteriophage recombinase for labeling multiple cell types simultaneously and a novel viral strategy for versatile and robust intersectional expression of any transgene. Together, our system will help researchers specifically target different cell types with multiple features in the same animal.
Engineered oncolytic bacteria HCS1 exerts high immune stimulation and safety profiles for cancer therapy
Authors: Yujie Sun, Yanxia Guo, Xiaoqing Liu, Jinling Liu, Honglai Sun, Zhongying Li, Min Wen, Sheng-Nan Jiang, Wenzhi Tan, Jin Hai Zheng
Journal: Theranostics (2023)

Background and rationale: Attenuated Salmonella typhimurium VNP20009 has been used to treat tumor-bearing mice and entered phase I clinical trials.However, its mild anticancer effect in clinical trials may be related to insufficient bacterial colonization and notable adverse effects with increasing dosages.Guanosine 5′-diphosphate-3′-diphosphate (ppGpp) synthesis-deficient Salmonella is an attenuated strain with good biosafety and anticancer efficacy that has been widely investigated in various solid cancers in preclinical studies.Integration of the advantages of these two strains may provide a new solution for oncolytic bacterial therapy.Methods: We incorporated the features of ΔppGpp into VNP20009 and obtained the HCS1 strain by deleting relA and spoT, and then assessed its cytotoxicity in vitro and antitumor activities in vivo. Results:In vitro experiments revealed that the invasiveness and cytotoxicity of HCS1 to cancer cells were significantly lower than those of the VNP20009.Additionally, tumor-bearing mice showed robust cancer suppression when treated with different doses of HCS1 intravenously, and the survival time and cured mice were dramatically increased.Furthermore, HCS1 can increase the levels of pro-inflammatory cytokines in tumor tissues and relieve the immunosuppression in the tumor microenvironments.It can also recruit abundant immune cells into tumor tissues, thereby increasing immune activation responses. Conclusion:The newly engineered Salmonella HCS1 strain manifests high prospects for cancer therapeutics and is a promising option for future clinical cancer immunotherapy.